Disubstituted morpholine, oxazepine or thiazepine derivatives, their preparation and their use as dopamine D4 receptor antagonists

ABSTRACT

The present invention relates to compounds of formula (I), any of it enantiomers, or any mixture thereof, or a pharmaceutically acceptable acid addition salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 11 , R 12 , R 13 , R 14  and R 15  each independently are hydrogen, alkyl, alkoxy, halogen, trifluoromethyl, nitro, cyano, amino, acyl, alkylamino, dialkylamino, aminocarbonyl, or acylamino; R5 is hydrogen, alkyl, alkoxyalkyl, or phenylalkyl; X is —CH 2 —Z—, Z—CH 2 —, NH—CO—, —CO—NH—, or —CH═CH—; wherein Z is O, S, CH 2 , or NH; Y is O, —CH 2 —W—, —W—CH 2 —; wherein W is O, or S; and n is 0, 1 or 2. The compounds are useful in the treatment of psychotic disorders.

This application is the national phase under 35 U.S.C. §371 of prior PCTInternational Application No. PCT/EP97/04587 which has an Internationalfiling date of Aug. 22, 1997 which designated the United States ofAmerica.

The present invention relates to novel pharmaceutically activedisubstituted heterocyclic compounds with high affinity for centraldopaminergic receptors. The compounds of the present invention areantagonists of the dopamine D₄ receptor and are useful in the treatmentof central nervous system disorders, especially psychotic disorders suchas schizophrenia.

BACKGROUND

Molecular biological techniques have revealed the existence of severalsubtypes of the dopamine receptor. The dopamine D₁ receptor subtype hasbeen shown to occur in at least two discrete forms. Two forms of the D₂receptor subtype, and at least one form of the D₃ receptor subtype, havealso been discovered. More recently, the D₄ (Van Tol et al., Nature(London), 1991, 350, 610) and D₅ (Sunahara et al., Nature (London),1991, 350, 614) receptor subtypes have been described.

The “dopamine hypothesis” of schizophrenia predicts an increasedactivity of dopamine neurotransmission in the brain. This hypothesis issupported by observations that drugs, such as amphetamine and cocaine,which indirectly stimulate the endogenous dopamine system by a dopaminerelease and uptake inhibition are capable of eliciting a psychosisresembling acute paranoid schizophrenia. The fact that classicalantipsychotic drugs produce their therapeutic effect by blocking centraldopamine D₂ receptors also lends credence to the “dopamine hypothesis”.It is however a serious drawback to the classical anti-psychotic drugsthat the blockage of dopamine D₂ receptors also leads to extrapyrimidalside-effects (EPS).

Clozapine is the only neuroleptic agent that improves the “positive” and“negative” symptoms of schizophrenia without producing EPS. Themechanism of action of Clozapine remains elusive, but has been proposedto be due, in part to a greater blockade of dopamine D₄ receptorscompared to D₂ receptors, and also to a blockade of serotonin 5-HT2Areceptors. It is considered that compounds which can interactselectively with the dopamine D₄ receptor subtype, whilst having a lesspronounced action at the D₂ subtype will be less prone to give theside-effects associated with classical antipsychotic drugs whilemaintaining a beneficial level of antipsychotic activity.

The compounds of the present invention are antagonists of the dopamineD₄ receptor they are predicted to be useful for the treatment ofpsychotic disorders such as schizophrenia.

Dopamine receptors are important for many functions in the animal body.For example, altered functions of these participate in the genesis ofpsychosis, addiction, sleep, feeding, learning, memory, sexualbehaviour, regulation of immunological responses and blood pressure.Since dopamine receptors control a great number of pharmacologicalevents, compounds that act preferentially on the dopamine D₄ receptormay exert a wide range of therapeutic effects in humans. The compoundsof the present invention may therefore also be useful for the treatmentof conditions such as sleep disorders, sexual disorders,gastrointestinal disorders, various forms of psychosis (affectivepsychosis, nonorganic psychosis), personality disorders, psychiatricmood disorders, conduct and impulse disorders, polydipsia, bipolardisorders, dysphoric mania, anxiety and related disorders, obesity,emesis, learning disorders, memory disorders, Parkinson's disease,depression, neuroleptic malignant syndrome, hypothalamic pituitarydisorders, congestive heart failure, chemical dependencies such as drugand alcohol addictions, vascular and cardiovascular disorders, oculardisorders (including glaucoma), dystonia, tardive dyskinesia, Gilles DeLa Tourette's Syndrome and other hyperkinesias, dementia, ischaemia,movement disorders such as akathesia, hypertension and diseases causedby a hyperactive immune system such as allergies and inflammation.

PRIOR ART

U.S. Pat. No. 4,088,814 describes certain morpholine derivatives havingthe formula

wherein A means ethylene or vinylene and X means optionally substitutedphenyl. The compounds are claimed to have psychotropic activity, e.g.antidepressant and sedative activity. Some compounds show analgesicactivity. Compounds described herein having a benzyl group attached inposition 4 are used as intermediates for the preparation of thetherapeutically active compounds.

GB patent No. 1.138.405 describes certain morpholine derivatives havingthe formula

wherein R¹ and R² means hydrogen or alkyl, R³ means hydrogen, alkyl,alkenyl, or cycloalkyl, and X means an optionally substituted arylradical. The compounds described herein possess depressant action on thecentral nervous system, and are said to be useful in the treatment ofanxiety, neurotic states and epilepsy. Some of the compounds are said topossess anti-depressant activity.

The compounds described herein having a arylalkyl group attached inposition 4 are used as intermediates for the preparation of thetherapeutically active compounds.

A well known compound disclosed in the above patent in Viloxazine or2-[(2-ethoxyphenoxy)methyl]morpholine. This compound have no or only lowaffinity for the central dopaminergic D₂ and D₄ receptors.

GB patent No. 1.310.236 describes certain morpholine derivatives whichare useful as intermediates for the preparation of therapeuticallyactive compounds.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide novel disubstitutedheterocyclic compounds and pharmaceutically-acceptable acid additionsalts thereof which are useful for the treatment of central nervoussystem disorders, or diseases responsive to the blockade of dopamine D₄receptors, especially psychotic disorders such as schizophrenia.

Another object of the present invention is to provide pharmaceuticalcompositions comprising the novel disubstituted heterocyclic compoundsbeing useful for above purposes.

Still another object of the present invention is to provide a method oftreating disorders or diseases responsive to the blockade of dopamine D₄receptors using the novel disubstituted heterocyclic compounds.

Additional objects will be obvious from the following description, andothers will be obvious to one skilled in the art.

SUMMARY OF THE INVENTION

The invention then, inter alia, comprises the following, alone or incombination:

A compound of the formula

any of its enantiomers, or any mixture thereof, or a pharmaceuticallyacceptable acid addition salt thereof,

wherein

R¹, R², R³, R⁴, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ each independently arehydrogen, alkyl, alkoxy, halogen, trifluoromethyl, nitro, cyano, amino,acyl, aminocarbonyl, or acylamino;

R⁵ is hydrogen, alkyl, alkoxyalkyl, phenylalkyl;

X is —CH₂—Z—, —Z—CH₂—, —NH—CO—, —CO—NH—, or —CH═CH—; wherein Z is O, S,CH₂ or NH;

Y is O, —CH₂—W—, —W—CH₂—; wherein W is O, or S;

and n is 0,1, or 2;

a compound as above which is

(±)-N-(4-chlorobenzyl)-2-(2-methoxy-4-chloro-phenoxymethyl)-morpholine,or (±)-2-[(4-chloro-2-methoxyphenoxy)methyl]-4-(4-chlorobenzyl)perhydrooxazepine or a pharmaceutically acceptable acid addition salt thereof.

a pharmaceutical composition, comprising an effective amount of acompound as any above, or a pharmaceutically acceptable acid additionsalt thereof, together with at least one pharmaceutically acceptablecarrier or diluent;

the use of a compound having the formula

any of its enantiomers, or any mixture thereof, or a pharmaceuticallyacceptable acid addition salt thereof,

wherein

R¹, R², R³, R⁴, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ each independently arehydrogen, alkyl, alkoxy, halogen, trifluoromethyl, nitro, cyano, amino,acyl, aminocarbonyl, or acylamino;

R⁵ is hydrogen, alkyl, alkoxyalkyl, phenylalkyl;

X is —CH₂—Z—, —Z—CH₂—, —NH—CO—, —CO—NH—, or —CH═CH—; wherein Z is O, S,CH₂ or NH;

Y is O, —CH₂—W—, —W—CH₂—; wherein W is O, or S;

and n is 0,1, or 2 for the manufacture of a medicament for the treatmentof a disorder or disease of a living animal body, including a human,which disorder or disease is responsive to the blockade of dopamine D₄receptors of the central nervous system;

the use of a compound as above for the manufacture of a medicament forthe treatment of psychotic disorders including schizophrenia;

the use asabove, wherein the compound employed isN-(4-chlorobenzyl)-2-(2-methoxy-4-chloro-phenoxymethyl)-morpholine, or(±)-2-[(4-chloro-2-methoxyphenoxy)methyl]-4-(4-chlorobenzyl)perhydrooxazepine or a pharmaceutically acceptable acid addition salt thereof;

a method for the treatment of a disorder or disease which is responsiveto the blockade of dopamine D₄ receptors of the central nervous systemcomprising administering to a living animal body, including a human, inneed thereof a therapeutically effective amount of a compound of theformula

any of its enantiomers, or any mixture thereof, or a pharmaceuticallyacceptable acid addition salt thereof,

wherein

R¹, R², R³, R⁴, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ each independently arehydrogen, alkyl, alkoxy, halogen, trifluoromethyl, nitro, cyano, amino,acyl, aminocarbonyl, or acylamino;

R⁵ is hydrogen, alkyl, alkoxyalkyl, phenylalkyl;

X is —CH₂—Z—, —Z—CH₂—, —NH—CO—, —CO—NH—, or —CH═CH—; wherein Z is O, S,CH₂ or NH;

Y is O, —CH₂—W—, —W—CH₂—; wherein W is O, or S;

and n is 0,1, or 2;

a method as above wherein the disorder or disease is a psychoticdisorder, including schizophrenia; and

a method for the preparation of a compound as above comprising the stepof reacting

a) reacting a compound having the formula

wherein R¹, R², R³, R⁴, R⁵, and X is as defined in claim 1, with acompound having the formula

wherein R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ is as defined in claim 1 and Hal ishalogen, to form a compound of the invention; or

b) reacting a compound having the formula

wherein R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ is as defined in claim 1 and Hal ishalogen, with a compound having the formula

wherein R¹, R², R³, R⁴ and R⁵ is as defined in claim 1, to form acompound of the invention, whereafter a compound of the invention isoptionally converted to another compound of the invention and/or to apharmaceutically acceptable salt of a compound of the invention.

Examples of pharmaceutically acceptable addition salts include inorganicand organic acid addition salts such as the hydrochloride, hydrobromide,phosphate, nitrate, perchlorate, sulphate, citrate, lactate, tartrate,maleate, fumarate, mandelate, benzoate, ascorbate, cinnamate,benzenesulfonate, methanesulfonate, stearate, succinate, glutamate,glycollate, toluene-p-sulphonate, formate, malonate,naphthalene-2-sulphonate, salicylate and the acetate. Such salts areformed by procedures well known in the art.

Other acids such as oxalic acid, while not in themselvespharmaceutically acceptable, may be useful in the preparation of saltsuseful as intermediates in obtaining compounds of the invention andtheir pharmaceutically acceptable acid addition salts.

Halogen is fluorine, chlorine, bromine or iodine.

Alkyl means a straight chain or branched chain of preferably one to sixcarbon atoms or cyclic alkyl of preferably three to seven carbon atoms,including but not limited to, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, t-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl; methyl, ethyl, propyl and isopropyl are particularlypreferred groups.

Acyl means -CO-alkyl wherein alkyl is as defined above.

Acylamino means Acyl-NH- wherein acyl is as defined above.

Amino is NH₂ or NH-alkyl or N-(alkyl)₂, wherein alkyl is as definedabove.

The compound of the invention are preferably oxazepines.

I.p. means intraperetoneally, which is a well known route ofadministration.

P.o. means peroral, which is a well known route of administration.

The compounds of the invention may be prepared in numerous ways. Thecompounds of the invention and their pharmaceutically acceptablederivatives may thus be prepared by any method known in the art for thepreparation of compounds of analogous structure, and as shown in therepresentative example which follow.

Starting materials for the processes described in the present patentapplication are known or can be prepared by known processes fromcommercially available materials.

A compound of the invention can be converted to another compound of theinvention using conventional methods.

The products of the reactions described herein are isolated byconventional means such as extraction, crystallization, distillation,chromatography, and the like.

Further, the compounds of this invention may exist in unsolvated as wellas in solvated forms with pharmaceutically acceptable solvents such aswater, ethanol the like. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of this invention.

It will be appreciated by those skilled in the art that the compounds ofthe present invention contain chiral centres and that such compoundsexist in the form of isomers (i.e. enantiomers). The invention includesall such isomers and any mixtures thereof including racemic mixtures.

A preferred embodiment of the invention comprises the compounds of claim1 wherein Y is —O— or —CH₂—O— and X is —CH₂—O— with S configuration.

The pure enantiomers can be obtained by the use of optically activestarting materials.

Racemic forms can also be resolved into the optical antipodes by knownmethods, for example, by separation of diastereomeric salts thereof withan optically active acid, and liberating the optically active aminecompound by treatment with a base. Another method for resolvingracemates into the optical antipodes is based upon chromatography on anoptically active matrix. Racemic compounds of the present invention canthus be resolved into their optical antipodes, e.g., by fractionalcrystallization of d- or l-(tartrates, mandelates, or camphorsulphonate)salts for example. The compounds of the present invention may also beresolved by the formation of diastereomeric amides by reaction of thecompounds of the present invention with an optically active activatedcarboxylic acid such as that derived from (+) or (−) phenylalanine, (+)or (−) phenylglycine, (+) or (−) camphanic acid or by the formation ofdiastereomeric carbamates by reaction of the compounds of the presentinvention with an optically active chloroformate or the like.

Additional methods for the resolvation of optical isomers, known tothose skilled in the art may be used, and will be apparent to theaverage worker skilled in the art. Such methods include those discussedby J. Jacques, A. Collet, and S. Wilen in “Enantiomers, Racemates, andResolutions”, John Wiley and Sons, New York (1981).

The compounds of the present invention exhibit a high affinity fordopamine D₄ receptors and a much lower affinity for dopamine D₂receptors. The affinity of certain compounds of the invention for thedopamine D₂ receptor and the dopamine D₄ receptor have been determinedby measuring the ability of the compounds to inhibit the binding of³H-spiperone to these receptors using the procedure described below:

INTRODUCTION

Dopamine is involved in several important functions, excitatory andinhibitory, via dopaminergic receptors in the central nervous system(CNS) and in the periphery. Dopaminergic systems are of particularinterest because of their role in the etiology and management of variousCNS disorders, such as Parkinson's disease and schizophrenia.

Dopamine receptors were originally classified into two main groups: D₁and D₂. The five currently cloned dopamine receptors fall into theseclasses. Thus, the D₁-like receptors include D₁ and D₅, while theD₂-like receptors include D₂, D₃ and D₄. Dopaminergic receptors arecoupled via two distinct G-proteins to intracellular signallingmechanisms. D₁ and D₂-like receptors are coupled respectively tostimulation and inhibition of the effector enzyme adenylyl cyclase,which produces the second messenger cAMP.

The D₂-like receptors can be labelled by the antagonist ³H-spiperone. Asthe ligand has the same affinity for D₂, D₃, and D₄ receptors, selectivebinding to i.e. D₄ receptors is only possible using recombinantreceptors.

TEST PROCEDURES

I) In vitro inhibition of ³H-spiperone binding to D₂ dopamine receptors

Tissue preparation: Preparations are performed at 0-4° C. unlessotherwise indicated. Corpus Striatum from male Wistar rats (150-200 g)is homogenized for 5-10 sec in 10 ml KH₂PO₄ (50 mM, pH 7.4) using anUltra-Turrax homogenizer. The suspension is centrifuged at 27,000×g for15 min. The supernatant is discarded and the pellet is resuspended in 50mM KH₂PO₄, pH 7.4 (2000 ml per g of original tissue) and used forbinding assays.

Assay: Aliquots of 0.5 ml tissue are added to 25 μl of test solution and25 μl of ³H-spiperone (0.2 nM, final concentration), mixed and incubatedfor 20 min at 37° C. Non-specific binding is determined using butaclamol(1 μM, final concentration). After incubation the samples are placed onice for 10 min. The assay is terminated by addition of 5 ml of ice-coldbuffer and poured directly onto Whatman GF/C glass fibre filters(presoaked in 0.1% PEI for at least 20 min) under suction andimmediately washed with 5 ml ice-cold buffer. The amount ofradioactivity on the filters is determined by conventional liquidscintillation counting. Specific binding is total binding minusnon-specific binding.

II) In vitro inhibition of ³H-spiperone binding to D_(4.2) dopaminereceptors (human recombinant)

Tissue preparation: Frozen membranes from Chinese Hamster Ovary (CHO)cells transfected with the human recombinant D_(4.2) dopamine receptor(RBI, D-195). Membranes are suspended in 10 mM Tris-HCl (pH 7.2)containing 2 mM EDTA, and stored tightly sealed at −80° C.

Assay: The membranes are thawed and diluted in incubation buffer (50 mMTris-HCl, pH 7.4, containing 120 mM NaCl, 5 mM KCl, 5 mM MgCl₂ and 1 mMEDTA) −0.25 ml of membranes to 4.75 ml of incubation buffer. Aliquots of100 μl of diluted membranes are added to 100 μl of test solution and 50μl of ³H-spiperone (0.5 nM, final concentration). Finally, 750 μlincubation buffer is added and the assay mixture is incubated for 60 minat 25° C. Non-specific binding is determined using haloperidol (1 μM,final concentration). After incubation the assay is terminated by rapidfiltration over GF/C glass fibre filters (presoaked in 0.1% PEI for atleast 20 min), then washed twice with 5 ml ice cold 50 mM Tris-HCl in0.9% NaCl at pH 7.4. The amount of radioactivity on the filters isdetermined by conventional liquid scintillation counting. Specificbinding is total binding minus non-specific binding.

RESULTS

The test values are given as IC₅₀ (the concentration of the testsubstance which inhibits the specific binding of ³H-spiperone by 50%).

The results obtained by testing certain compounds of the invention arepresented in table 1:

TABLE 1 Compound D₄(μM) D₂(μM)(±)-N-(4-chlorobenzyl)-2-(2-methoxy-4-chloro- 0.004  >10.00phenoxymethyl)-morpholine (±)-2-[(4-chloro-2-methoxyphenoxy)-methyl]-0.0025 >10.00 4-(4-chlorobenzyl)perhydro oxazepine

Pharmaceutical compositions

While it is possible that, for use in therapy, a compound of theinvention may be administered as the raw chemical, it is preferable topresent the active ingredient as a pharmaceutical formulation.

The invention thus further provides pharmaceutical formulationscomprising a compound of the invention or a pharmaceutically acceptablesalt or derivative thereof together with one or more pharmaceuticallyacceptable carriers therefor and, optionally, other therapeutic and/orprophylactic ingredients. The carrier(s) must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not deleterious to the recipient thereof.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, sub-cutaneous and intravenous) administrationor in a form suitable for administration by inhalation or insufflation.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalcompositions and unit dosages thereof, and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, or capsules filled with thesame, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. Formulations containingten (10) milligrams of active ingredient or, more broadly, 0.1 to onehundred (100) milligrams, pre tablet, are accordingly suitablerepresentative unit dosage forms.

The compounds of the present invention can be administered in a widevariety of oral and parenteral dosage forms. It will be obvious to thoseskilled in the art that the following dosage forms may comprise, as theactive component, either a compound of the invention or apharmaceutically acceptable salt of a compound of the invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, table disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired.

The powders and tablets preferable contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid foam preparations include solutions, suspensions, and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

The compounds according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The compositions may take suchforms as suspensions, solutions, or emulsions in oily or aqueousvehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solution or by lyophilisation from solution, for constitutionwith a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active components in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavours, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also contain one or more emulsifying agents,stabilising agents, dispersing agents, suspending agents, thickeningagents, or colouring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavoured base, usually sucroseand acacia or tragacanth; pastilles comprising the active ingredient inan inert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multidose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomising spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurized pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivative such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 5 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization.

When desired, formulations adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration are preferred compositions.

Methods of treating

The compounds of this invention possess potent dopamine D₄ receptorblocking activity. This property make the compounds of the presentinvention extremely useful in the treatment of psychotic disorders suchas schizophrenia as well as other disorders sensitive to the blockade ofdopamine D₄ receptors. The compounds of this invention may accordinglybe administered to a living animal body, including a human, in need oftreatment, alleviation, or elimination of an indication associated withor responsive to the blockade of dopamine receptors, especially thedopamine D₄ receptor. This includes especially schizophrenia and otherpsychotic disorders. Suitable dosage range are 0.1-500 milligrams daily,and especially 10-17 milligrams daily, administered once or twice a day,dependent as usual upon the exact mode of administration, form in whichadministered, the indication toward which the administration isdirected, the subject involved and the body weight of the subjectinvolved, and further the preference and experience of the physician orveterinarian in charge.

The following examples will illustrate the invention further, however,they are not to be construed as limiting.

EXAMPLES

General: All reactions involving air sensitive reagents or intermediateswere performed under nitrogen.

Example 1

N-(4-Chlorobenzyl)-N-(2-hydroxyethyl)amine

Ethanolamine (56.9 g, 931 mmol) and sodium hydroxide (7.44 g, 186 mmol)were mixed in isopropanol (50 ml) and 4-chlorobenzyl chloride (30 g, 186mmol) was added at such a rate that a mild reflux was achieved. Themixture was then refluxed for another 30 min. Evaporation of the solventwas followed by the addition of methylene chloride (50 ml). The solidswere filtered off and the solvent was evaporated from the filtrate. Theresidual oil was distilled under oil pump vacuum and the fraction at125-126° C. (0.1 mm Hg) was collected. Yield 27 g, 78%.

N-(4-Chlorobenzyl)-N-(3-hydroxypropyl)amine

N-(4-Chlorobenzyl)-N-(3-hydroxypropyl)amine was prepared analogouslystarting with 3-hydroxypropylamine. bp 128-130° C. 0.1 mm Hg. Yield 29%.

Example 2

(±)-4-(4-Chlorobenzyl)-2-(chloromethyl)perhydro-1,4-oxazepin.

(±)-4-(4-Chlorobenzyl)-2-(chloromethyl)perhydro-1,4-oxazepin wasprepared analogously to the method for the preparation of(±)-4-benzyl-2-(chloro-methyl)perhydro-1,4-oxazepin described in K.Araki et al. J. Med. Chem. 36, 1356 (1993), usingN-(4-Chlorobenzyl)-N-(3-hydroxypropyl)amine as starting material. Yield29%.

Example 3

(±)-4-Benzyl-2-chloromethylmorpholine

(±)-4-Benzyl-2-chloromethylmorpholine was prepared according to F.Loftus, Synth. commun. 10, 59 (1980).

(±)-4-(4-Chlorobenzyl)-2-chloromethylmorpholine

The title compound was prepared analogously usingN-(4-chlorobenzyl)-N-(2-hydroxyethyl)amine and epichlorohydrin as thestarting material. bp 106-120° C. at 0.3 mm Hg.

Example 4

R-4-(4-Chlorobenzyl)-2-chloromethylmorpholine andS-4-(4-chlorobenzyl)-2-chloromethylmorpholine

R-4-(4-Chlorobenzyl)-2-chloromethylmorpholine andS-4-(4-chlorobenzyl)-2-chloromethylmorpholine was prepared analogouslyto the preparation of R- andS-4-(4-fluorobenzyl)-2-chloromethylmorpholine as described in T. Morie,S. Kato, H. Harada, and J. Matsumoto Heterocycles, 38 (1994).

Example 5

(±)-4-Benzyl-2-[(2-ethoxyphenoxy)-methyl]morpholine.

4-Benzyl-2-[(2-ethoxyphenoxy)-methyl]morpholine was prepared accordingexample 18 (below). The product was obtained as an oil.

2-[(2-Ethoxyphenoxy)-methyl]morpholine hydrochloride.

The title compound was prepared by hydrogenation of(±)-4-benzyl-2-[(2-ethoxyphenoxy)-methyl]morpholine over 5% Pd/C inethanol: 1 M aqueous HCl 3:1. mp 176-179° C. Yield 96%.

Example 6

Anisole (10 g, 70.1 mmol) was dissolved in carbon tetrachloride (200 ml)and iron powder (6.0 g, 105 mmol Fe)was added. Bromine (4 ml, 77.1 mmol)was added at 0° C. The temperature was allowed rise to room temperatureover one hour. Washing with aqueous sodium sulfite three times wasfollowed by washing with aqueous sodium hydroxide (4 M). Drying overmagnesium sulfate and evaporation gave the title compound. Yield 5.63 g,36%.

Example 7

5-Chloro-2-methoxy benzeneboronic acid.

A solution of 2-bromo-4-chloroanisole (5.0 g, 22.6 mmol) in dry THF (60ml) under nitrogen was cooled to −70° C. and n-butyl lithium (12.4 ml ofa 2.0 M solution in hexanes, 24.8 mmol) was added. After 10 min. at −70°C. tributyl borate (8.5 ml, 31.4 mmol) was added and the temperature wasallowed to rise to room temperature overnight. Aqueous hydrochloric acid(40 ml, 2 M) was added and the product was extracted with 2×60 ml ether.The ethereal phase was extracted with aqueous sodium hydroxide (2×40 ml,1 M). Acidification with concentrated HCl during ice-cooling gave aprecipitate that was dissolved in ether. Drying over magnesium sulfateand evaporation of the solvent gave the title compound. Yield 1.93 g,46%.

Example 8

5-Chloro-2-methoxyphenol.

A solution of 5-chloro-2-methoxy benzeneboronic acid (1.9 g, 10 mmol) inhydrogen peroxide (2.04 ml, 30% solution) and ethanol 40 ml was refluxedfor 30 min. Water was added and the product was extracted with twoportions of ethylacetate. Drying over magnesium sulfate and evaporationof the solvent gave the product as an oil. Yield 1.05 g, 65%.

Example 9

4-Iodo-2-methoxyphenol

4-Iodo-2-methoxyphenol was prepared according to the method described byK. J. Edgar and N. Falling, J. Org. Chem. 55, 5287 (1990). Guaiacol(50.0 g, 402 mmol), sodium iodide (60.5 g, 402 mmol) was dissolved inmethanol (800 ml) and cooled to 0° C., and sodium hydroxide (16.0 g, 402mmol) was added at such a rate that the temperature did not exceed 5° C.An aqueous solution of sodium hypochlorite (750 ml, 7.2% solution, 402mmol) was added during 45 min. The temperature was not allowed to exceed0° C. After completed addition it was stirred for another 10 minutes at0° C. First aqueous hydrochloric acid (100 ml, 4 M solution) and thensodium sulfite (200 ml saturated aqueous solution) was added. Theproduct was extracted with ether was followed by drying over magnesiumsulfate. Evaporation of the solvent was followed by distillation and thefraction at 105-106° C. at 0.1 mm Hg was collected. Yield 55 g, 54%.

Example 10

2-Chloro-4-hydroxy-5-methoxybenzoic acid

2-Chloro-4-hydroxy-5-methoxybenzoic acid was prepared according to L. C.Raiford and D. J. Potter J. Am. Chem. Soc. 55, 1682 (1933).

Example 11

4-Acetoxy-2-chloro-5-methoxybenzoic acid

4-Acetoxy-2-chloro-5-methoxybenzoic acid was prepared by acetylation of2-chloro-4-hydroxy-5-methoxybenzoic acid.

Example 12

5-Chloro-4-cyclopropylaminocarbonyl-2-methoxyphenol

A solution of 4-acetoxy-2-chloro-5-methoxybenzoic acid (8.6 g, 35.2mmol) and triethylamine (8.9 g, 88 mmol) in dry dichloromethane (100 ml)was cooled to 0° C. and ethylchloroformate (7.6 g, 70 mmol) was added atsuch a rate that the temperature stayed below 5° C. After 1 hcyclopropylamine (6.0 g, 105 mmol) was added. After stirring overnightat room temperature the organic phase was washed with water (2×200 ml).Drying over magnesium sulfate was followed by reduction of the solventvolume to half. Petrol ether was added and the product was filtered off.Yield 570 mg, 6.7%, mp 214-216° C.

Example 13

2-(2-methoxy-1-ethoxy)-phenol

Catechol (10.0 g, 91 mmol), bromoethylmethylether (12.6 g, 91 mmol), andpotassium carbonate (12.6 g, 91 mmol) were mixed in ethanol (100 ml) andrefluxed for 15 h. The solvent was evaporated and dichloromethane (200ml) was added. The inorganics were filtered off and the solvent wasremoved in vacuum. Chromatography on silica gel with 0.5% methanol indichloromethane as the eluent gave the title compound. Yield 4.5 g, 29%.

Example 14

2-Epoxy-1-(2-methoxyphenoxy)-propane

Guaiacol (8.6 g, 69 mmol), potassium t-butoxide (7.8 g, 69 mmol),epichlorohydrin (19.3 g, 209 mmol), and 18-crown-6 (0.8 g) were mixed int-butanol (100 ml) and heated to 50° C. for 2 h. Water was added and theproduct was extracted with two portions of dichlorometane. Washing withwater, twice, was followed by drying and evaporation. Quantitativeyield.

Example 15

2-[(2-Methoxyphenoxy)methyl]-morpholine

A mixture of 2-epoxy-1-(2-methoxyphenoxy)-propane (13.0 g, 72 mmol),2-aminoethylhydrogensulfate (51 g, 361 mmol), potassium hydroxide (41 g,722 mmol) in isopropanol (300 ml) and water 100 ml was refluxed for 8 h.Water was added and the product was extracted with two portions ofethylacetate. Drying and evaporation gave a crude product that was usedwithout further purification. Yield 9.2 g.

Example 16

2-[(5-Chlorobenzoxazolin-2-one-1-yl)-methyl]-4-(4-chlorobenzyl)-morpholine

2-[(5-Chlorobenzoxazolin-2-one-1-yl)-methyl]-4-(4-chlorobenzyl)-morpholinewas prepared from 5-chlorozoxazone and(±)-4-(4-chlorobenzyl)-2-chloromethyl-morpholine according to example18. mp 160-164° C. (As the oxalate). The free base was used in furtherreactions.

Example 17

(±)2-[(2-methoxyphenoxy)methyl]-4-(4-trifluoromethylbenzyl)morpholineoxalic acid salt.

The crude 2-[(2-methoxyphenoxy)methyl]morpholine (2.0 g, 9.0 mmol) wasmixed with 4-trifluoromethylbenzylbromide (2.58 g, 10.8 mmol), potassiumcarbonate (6.84 g, 49.5 mmol) in ethanol (50 ml) and refluxed for 3.5 h.Water was added and the product was extracted with 2 portions of ethylacetate. Drying and evaporation gave the crude free base. Dissolution inether and precipitation with oxalic acid gave a salt that was purifiedby recrystallization from ethanol and then THF. Yield 430 mg, 10%, mp101-108° C.

The following products were prepared analogously:

(±)-4-Benzyl-2-[(2-methoxyphenoxy)methyl]morpholine oxalic acid salt, mp124-133° C.

(±)-4-(3-Chlorobenzyl-2-[(2-methoxyphenoxy)methyl]morpholine oxalic acidsalt, mp 132-136° C.

(±)-4-(4-Chlorobenzyl-2-[(2-methoxyphenoxy)methyl]morpholine oxalic acidsalt, mp 139-142° C.

(±)-4-Benzyl-2-[(5-chloro-2-methoxyphenoxy)methyl]morpholine oxalic acidsalt, mp 166-168° C.

(±)-4-Benzyl-2-[(4-iodo-2-methoxyphenoxy)methyl]morpholine oxalic acidsalt, mp 160-163° C.

(±)-4-(3,4-Dichlorobenzyl)-2-[(2-methoxyphenoxy)methyl]morpholine oxalicacid salt, mp 140-143° C.

(±)-4-(4-Chlorobenzyl-2-[(2-ethoxy-4-iodophenoxy)methyl]morpholine, mp86-90° C.

Example 18

(±)-4-(4-Chlorobenzyl)-2-[(4-chloro-2-methoxyphenoxy)methyl]morpholineoxalic acid salt. A mixture of(±)-4-(4-chlorobenzyl)-2-chloromethylmorpholine (10.0 g, 38.5 mmol),4-chloro-2-methoxyphenol (9.0 g, 58 mmol), potassium ethoxide (6.5 g, 77mmol), and 18-crown-6 (10.2 g, 38.5) was refluxed in toluene (100 ml)for 34 h. Water (200 ml) was added and the phases were separated. Dryingand evaporation of the toluene phase was followed by columnchromatography on silica gel with 3% ethanol in dichloromethane aseluent. The free base was dissolved in ether and precipitated withoxalic acid to give the title compound. Yield 10.3 g, 57%, mp 133-139°C.

The following compounds were prepared analogously:

(±)-4-(4-Chlorobenzyl-2-[(5-nitro-2-methoxyphenoxy)methyl]morpholineoxalic acid salt, mp 176-177° C.

(±)-4-(4- Chlorobenzyl-2-[(2-ethoxyphenoxy-methyl]morpholine oxalic acidsalt, mp 122-127° C.

(±)-4-Benzyl-2-[(2-benzyloxyphenoxy)methyl]morpholine oxalic acid salt.mp 79-84° C.

(±)-4-(4-Chlorobenzyl-2-[(5-chloro-4-cyclopropylaminocarbonyl-2-methoxyphenoxy)methyl]morpholine.mp 159-162° C.

(±)-4-(4-Chlorobenzyl-2-[(2-methoxyethoxyphenoxy)methyl]morpholineoxalic acid salt. mp 122-127° C.

(±)-4-(4-(Chlorobenzyl-2-[(2-ethoxyphenoxy)methyl]perhydro oxazepine.Oil.

(±)-4-(4-Chlorobenzyl)-2-[(5-chloro-2-methoxyphenylamino)-methyl]morpholineoxalic acid salt was prepared using 5-chloro-2-methoxyaniline instead ofa phenol . A reaction temperature of 40° C. was used in this case. mp169-171° C.

(±)-2-(2,6-Dimethoxyphenoxy)methyl]-4-(4-chlorobenzyl)-morpholine oxalicacid salt. mp 105-107° C.

(±)-4-(4-Chlorobenzyl)-2-[(2-isopropoxyphenoxy)methyl]morpholine oxalicacid salt. mp 89-90° C.

(±)-2-[(2,3-Dimethoxyphenoxy)methyl]-4-(4-chlorobenzyl)-morpholineoxalic acid salt. mp 139-141° C.

(±)-4-(4-Chlorobenzyl)-2-[(4-chloro-2-ethoxyphenoxy)methyl]morpholine.The product was isolated as the free base. mp 88-90° C.

(±)-4-(4-Chlorobenzyl)-2-[(2-methoxyphenylthio)methyl]morpholine oxalicacid salt. mp 101-103° C.

(±)-4-(4-Chlorobenzyl-2-[(4-chloro-2-ethoxyphenoxy)methyl]perhydrooxazepine oxalic acid salt, mp 77-81° C.

(±)-4-(4-Chlorobenzyl-2-[(5-chloro-2-ethoxyphenoxy)methyl]morpholine mp85-87° C.

(±)-2-(2-Acetyl-4-chlorophenoxy)methyl]-4-(4-chlorobenzyl)perhydrooxazepine oxalic acid salt. mp 148-151° C.

(±)-2-[(4-chloro-2-methoxyphenoxy)methyl]-4-(4-chlorobenzyl)perhydrooxazepine oxalic acid salt. mp 127-129° C.

(R)-4-(4-Chlorobenzyl)-2-[(4-chloro-2-methoxyphenoxy)methyl]morpholineoxalic acid salt. Was prepared usingR-4-(4-chlorobenzyl)-2-chloromethylmorpholine as starting material. mp150-151° C.

(S)-4-(4-Chlorobenzyl)-2-[(4-chloro-2-methoxyphenoxy)methyl]morpholineoxalic acid salt. Was prepared usingS-4-(4-chlorobenzyl)-2-chloromethylmorpholine as starting material.

(±)-2-[(2-methoxy-5-nitrophenoxy)methyl]-4-(4-chlorobenzyl)perhydrooxazepine oxalic acid salt. mp 140-143°

Example 19

(±)-1-[(4-chlorobenzyl)morpholin-2-yl]-2-(2-methoxyphenyl)-ethene oxalicacid salt.

A mixture of N-(4-chlorobenzyl)-N-(2-hydroxyethyl) amine (2.00 g, 10.8mmol) and cis-1,4-diacetoxy-2-buten (2.78 g, 16.2 mmol), triethylamine(3.26 g, 32.3 mmol), tetrakis triphenylphosphino palladium(O) (0.31 g,0.27 mmol) in THF (20 ml) was refluxed overnight. DMF (10 ml) was addedand the THF was stripped off in vacuum. Addition of 2-iodoanisole (3.8g, 16.2 mmol) and diisopropylethylamine (2.8 g, 21.6 mmol) was followedby heating to 130° C. overnight. Ether was added and the organics werewashed twice with aqueous sodium hydroxide (1 M). Chromatography onsilica gel with dichloromethane with 1% methanol as the eluent gave thefree base. Dissolution in ether and precipitation with oxalic acid gavethe title compound. Yield 1.0 g, 21%. mp 178-180° C.

(±)-4-(4-Chlorobenzyl)-2-[2-(2-methoxyphenoxy)eth-1-yl]morpholine oxalicacid salt. Was prepared by the hydrogenation of(±)-1-[(4-chlorobenzyl)morpholin-2-yl]-2-(2-methoxyphenyl)ethene. mp167-169° C.

Example 20

(±)-2-[(4-Acetyl-2-methoxyphenoxy)methyl]-4-benzylmorpholine oxalic acidsalt. (±)-4-Benzyl-2-[(4-iodo-2-methoxyphenoxy)methyl]morpholine (360mg, 0.82 mmol), 1-methoxyvin-1-yl trimethyltin (528 mg, 2.4 mmol), andpalladium bis(triphenylphosphine)palladium(II)chloride (36 mg, 0.052mmol) was refluxed in THF (15 ml) for 24 h. Water was added and wasfollowed by extraction twice with ethyl acetate. The solvent wasevaporated and the residue was stirred in aqueous hydrochloric acid (25ml, 1 M) and methanol (10 ml) at 50° C. for 1 h. The product wasextracted with ethyl acetate. Drying and evaporation of the solvent wasfollowed by chromatography. The product was dissolved in ether andprecipitated as the oxalate. Yield 40 mg. mp 122-127° C.

Example 21

(±)2-[(5-Amino-2-methoxyphenoxy)methyl]-4-(4-chlorobenzyl)-morpholineoxalic acid salt. Prepared by the catalytic hydrogenation of(±)-4-(4-chlorobenzyl)-2-[(5-nitro-2-methoxyphenoxy)methyl]morpholine.mp 80-110° C.

Example 22

(±)-4-(4-Chlorobenzyl)-2-[(4-chloro-2-hydroxyphenylamino)-methyl]morpholineoxalic acid salt. To solution of2-[(5-chlorobenzoxazolin-2-one-1-yl)methyl]-4-(4-chlorobenzyl)morpholine(1.5 g, 3.8 mmol) in dimethoxyethane (8 ml) was added aqueous sodiumhydroxide (3.8 ml of a 4 M solution, 15.3 mmol). After being stirred at50° C. for 1 h water was added and the solids were filtered off. Thefiltrate was extracted twice with ethyl acetate. Drying and evaporationgave the free base. The product was then precipitated by dissolution inether and addition of a saturated ethereal solution of oxalic acid.Yield 1.05 g, 61%. mp 177-179° C.

Example 23

(±)-4-(4-nitrobenzyl)-2-[(2-ethoxyphenoxy)methyl]morpholine oxalic acidsalt. A mixture of (±)-2[(2-ethoxyphenoxy)methyl]morpholinehydrochloride (3.0 g, 11.0 mmol) and 4-nitrobenzylbromide (2.37 g, 11.0mmol) and potassium carbonate (1.52 g, 11.0 mmol) in DMF (30 ml) washeated to 80° C. for 4 h. Aqueous solution hydroxide (50 ml) was addedand the product was extracted twice with ether. Drying and evaporationgave the crude product. Chromatography on a silica gel withdichloromethane +3% ethanol as the eluent. The product was dissolved inether and precipitated as the oxalate. Yield 72% mp 113-114° C.

Example 24

(±)-4-(4-Chlorobenzyl)-2-[(4-cyano-2-ethoxyphenoxy)methyl]morpholineoxalic acid salt. A mixture of(±)-4-(4-chlorobenzyl)-2-[(2-ethoxy-iodophenoxy)methyl]-morpholine (1.0g, 2.1 mmol), zinc cyanide (0.17 g, 1.4 mmol) andtetrakis(triphenylphosphino)palladium(O) (349 mg, 0.3 mmol) in DMF (15ml) was heated to 80° C. for 3 h. Water was added and the solids werefiltered off. The filtrate was extracted twice with ethyl acetate.Drying over magnesium sulfate was followed by evaporation. The crudeproduct was dissolved in ether and an ethereal solution of oxalic acidwas added to precipitate the product.

mp 133-138° C.

What is claimed is:
 1. A compound of formula (I)

any of its enantiomers of any mixture thereof, or a pharmaceuticallyacceptable acid addition salt thereof, wherein: R¹, R², R³, R⁴, R¹¹,R¹², R¹³, R¹⁴ and R¹⁵ each independently are hydrogen, alkyl, alkoxy,halogen, trifluoromethyl, nitro, cyano, amino, aminoalkyl, aminodialkyl,acyl, aminocarbonyl, or acylamino; R⁵ is hydrogen, alkyl, alkoxyalkyl,or phenylalkyl; X is —CH₂—Z— or —Z—CH₂—, wherein Z is O, S, CH₂, or NH;Y is —CH₂—W—, —W—CH₂—; wherein W is O; and n is 0, 1 or
 2. 2. Thecompound of claim 1 wherein Y is —CH₂O— and X is —CH₂—O— with Sconfiguration.
 3. The compound of claim 1 or 2 wherein R¹¹, R¹², R¹³,R¹⁴ and R¹⁵ are not hydrogen at the same time.
 4. The compound of claim1 which is(±)-2-[(4-chloro-2-methoxyphenoxy)methyl]-4-(4-chlorobenzyl)perhydrooxazepine or a pharmaceutically acceptable acid addition salt thereof.5. A pharmaceutical composition comprising an effective amount of atleast one compound of claim 1, and at least one pharmaceuticallyacceptable carrier or diluent.
 6. A method for the treatment of sleepdisorders, sexual disorders, gastrointestinal disorders, psychosis,personality disorders, psychiatric mood disorders, conduct disorders,impulse disorders, psychiatric mood disorders, schizoaffectivedisorders, bipolar disorders, anxiety disorders, learning disorders,memory disorders, hypothalamic pituitary disorders, vascular disorders,cardiovascular disorders, ocular disorders, movement disorders, anddiseases caused by hyperactive immune systems comprising administeringto a living animal body, including a human, in need thereof atherapeutically effective amount of at least one compound of claim
 1. 7.A method for the treatment of schizophrenia, polydipsia, dysphoricmania, anxiety, obesity, emesis, Parkinson's disease, depression,neuroleptic malignant syndrome, congestive heart failure, chemicaldependence on drugs, chemical dependence on alcohol, glaucoma, dystonia,tardive dyskinesia, Gilles De La Tourette's syndrome, dementia,ischaemia, akathesia, hypertension, allergies and inflammationcomprising administering to a living animal body, including a human, inneed thereof a therapeutically effective amount of at least one compoundof claim 1.